Retroviruses, like other RNA viruses, exist in nature not as a single genomic species, but as a complex mixture of closely related genomes. During infection in the natural host, the virus population is continually shaped by selective forces. Minor genomic variations may significantly alter the virus phenotype, and thus provide the substrate on which selective pressures act. Our understanding of the aspects of virus phenotype that drive selection in natural retroviral infection is limited. Feline leukemia virus (FeLV) is an excellent model with which to explore the selective pressures operative in natural retroviral infection because FeLV is a naturally occurring retrovirus endemic in an outbreeding mammalian species, the domestic cat. FeLV is a genetically complex family of viruses, infection with which is associated with clinically variable outcome. In these respects, FeLV infection emulates viral infection in humans. In previous studies, a unique FeLV isolate, termed FeLV-945, was identified in non-thymic lymphomas of the multicentric type. FeLV-945 contains unique sequence elements that are precisely conserved among independent isolates in a geographic cluster. Based on the results of preliminary studies, specific mechanisms are hypothesized that may account for the precise conservation and apparent phenotypic advantage of FeLV-945. Specifically, it is hypothesized that the distinctive structural features of FeLV-945 confer a selective growth advantage to the virus in vivo, and/or a survival advantage to the infected cell. To test this possibility, virus replication will be quantified in infected tissues longitudinally during infection, and proto-oncogenes activated by FeLV-945 in lymphomas will be identified. It is further hypothesized that a requirement for specific protein binding to the unique sequence elements of the FeLV-945 LTR promotes its precise conservation. This possibility will be tested through a structural and functional analysis of protein binding sites in the unique sequence elements. Finally, it is hypothesized that the unique sequence elements of FeLV-945 SU confer a selective phenotypic advantage in altered receptor interactions and/or growth kinetics. This possibility will be tested using a novel single-cycle infection assay. The results will be considered in the context of the range of FeLV variation in natural multicentric lymphomas.